Carlier Jeremy, Malaca Sara, Huestis Marilyn A, Tagliabracci Adriano, Tini Anastasio, Busardò Francesco P
Department of Biomedical Sciences and Public Health, Section of Legal Medicine, Unit of Forensic Toxicology, Marche Polytechnic University, Ancona, Italy.
Institute of Emerging Health Professions, Thomas Jefferson University, Philadelphia, PA, USA.
Expert Opin Drug Metab Toxicol. 2022 Dec;18(12):831-840. doi: 10.1080/17425255.2022.2166826. Epub 2023 Jan 26.
4-Hydroxy--methylpropyltryptamine (4-OH-MPT) is a psychedelic tryptamine whose use is regulated in several countries. Due to unspecific effects, consumption can be ascertained only through toxicological analyses. However, the trace amounts of tryptamines are usually challenging to detect in biological samples. 4-OH-MPT metabolism was characterized to identify optimal metabolite markers of intake in clinical/forensic toxicology.
4-OH-MPT was incubated with 10-donor-pooled human hepatocytes to simulate conditions; samples were analyzed by liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS), and data were processed with Compound Discoverer from Thermo Scientific. LC-HRMS/MS and data mining were supported by metabolite predictions (GLORYx).
Three phase I and four phase II metabolites were identified, including -oxidation and -demethylation at the alkylamine chain, and -glucuronidation and sulfation at the hydroxylindole core.
4-OH-MPT metabolic fate was consistent with the human metabolism of tryptamine analogues: we suggest 4-OH-MPT--oxide and 4-hydroxy--propyltryptamine (4-OH-PT) as metabolite biomarkers of 4-OH-MPT consumption after glucuronide/sulfate hydrolysis in biological samples to improve detection of 4-OH-MPT and phase I metabolites; 4-OH-MPT-glucuronide is suggested as an additional biomarker when hydrolysis is not performed. Further research on the metabolism of structural analogues is necessary to evaluate the specificity of 4-OH-MPT metabolite biomarkers.
4-羟基-N-甲基丙基色胺（4-OH-MPT）是一种致幻色胺，在多个国家其使用受到管制。由于其作用不具有特异性，只能通过毒理学分析来确定是否有人摄入。然而，在生物样本中通常很难检测出色胺的痕量。对4-OH-MPT的代谢进行了表征，以确定临床/法医毒理学中摄入的最佳代谢物标志物。
将4-OH-MPT与10名供体的混合人肝细胞一起孵育以模拟相关条件；通过液相色谱-高分辨率串联质谱（LC-HRMS/MS）对样品进行分析，并用赛默飞世尔科技的Compound Discoverer处理数据。LC-HRMS/MS和数据挖掘得到代谢物预测（GLORYx）的支持。
鉴定出三种I相和四种II相代谢物，包括烷基胺链上的ω-氧化和N-去甲基化，以及羟基吲哚核心上的O-葡萄糖醛酸化和硫酸化。
4-OH-MPT的代谢命运与色胺类似物的人体代谢一致：我们建议将4-OH-MPT-N-氧化物和4-羟基-N-丙基色胺（4-OH-PT）作为生物样本中葡萄糖醛酸/硫酸盐水解后4-OH-MPT摄入的代谢物生物标志物，以提高对4-OH-MPT及其I相代谢物的检测；当不进行水解时，建议将4-OH-MPT-葡萄糖醛酸作为额外的生物标志物。有必要对结构类似物的代谢进行进一步研究，以评估4-OH-MPT代谢物生物标志物的特异性。
